191 ALS AND OTHER MOTOR NEURON DISEASES
Harrison’s Manual of Medicine
ALS AND OTHER MOTOR NEURON DISEASES
Amyotrophic lateral sclerosis (ALS) is the most important of the motor neuron diseases (Table 191-1). ALS is caused by degeneration of motor neurons at all levels of the CNS, including anterior horns of the spinal cord, brainstem motor nuclei, and motor cortex. Familial ALS (FALS) represents 5–10% of the total and is inherited as an autosomal dominant disorder. Syndromes clinically indistinguishable from classic ALS may result rarely from intoxication with mercury, lead, or aluminum and in hyperparathyroidism, thyrotoxicosis, immunologic or paraneoplastic mechanisms, and hereditary biochemical disorders. Tumors near the foramen magnum, high spinal cord tumors, cervical spondylosis, chronic polyradiculopathies, polymyositis, spinal muscle atrophies, and diabetic, syphilitic, and postpolio amyotrophies can all produce signs and symptoms similar to those seen in ALS and should be carefully considered in differential diagnosis (Table 191-2).
Table 191-1 Sporadic Motor Neuron Diseases
Table 191-2 Etiology and Investigation of Motor Neuron Disorders
Onset is usually midlife, with most cases progressing to death in 3–5 years. Common initial symptoms are weakness, muscle wasting, stiffness and cramping, and twitching in muscles of hands and arms. Legs are less severely involved than arms, with complaints of leg stiffness, cramping, and weakness common. Symptoms of brainstem involvement include dysarthria and dysphagia.
Lower motor neuron disease results in weakness and wasting that often first involves intrinsic hand muscles but later becomes generalized. Fasciculations occur in involved muscles, and fibrillations may be seen in the tongue. Hyperreflexia, spasticity, and upgoing toes in weak, atrophic limbs provide evidence of upper motor neuron disease. Brainstem disease produces wasting of the tongue, difficulty in articulation, phonation, and deglutition, and pseudobulbar palsy (e.g., involuntary laughter, crying). Important additional features that characterize ALS are preservation of intellect, lack of sensory abnormalities, and absence of bowel or bladder dysfunction.
EMG provides objective evidence of muscle denervation as well as of involvement of muscles innervated by different peripheral nerves and nerve roots. Myelography, CT, or MRI may be useful to exclude compressive lesions. CSF is usually normal. Muscle enzymes (e.g., CK) may be elevated. Pulmonary function studies may aid in management of ventilation. Useful tests to exclude other diseases can include urine and serum screens for heavy metals, thyroid functions, serum immunoelectrophoresis, lysosomal enzyme screens, anti-GM1 antibodies, vitamin B12 levels, VDRL, CBC, ESR, and serum chemistries. In FALS, one subset has mutations in the gene encoding the cytosolic enzyme superoxide dismutase 1 (SOD1).
Weakness of ventilatory muscles leads to respiratory insufficiency; dysphagia may result in aspiration pneumonia and compromised energy intake.
There is no treatment capable of arresting ALS. The drug riluzole produces modest lengthening of survival; in one trial the survival rate at 18 months with riluzole (100 mg/d) was similar to placebo at 15 months. It may act by diminishing glutamate release and thereby decreasing excitotoxic neuronal cell death. Side effects of riluzole include nausea, dizziness, weight loss, and elevation of liver enzymes. In a single study, insulin-like growth factor (IGF- 1) was found to slow ALS progression modestly, but the effect was not confirmed in a second trial; IGF-1 is not routinely available as an ALS treatment at this time. Clinical trials of several other agents are in progress, including brain-derived neurotrophic factor, glial-derived neurotrophic factor, the anti- glutamate compound topiramate, and creatine. In a single study from France, vitamin E was beneficial in sporadic ALS. Several types of secondary motor neuron disorders that resemble ALS are treatable (Table 191-2). All pts should have a careful search for these disorders. Supportive care can include home care ventilation and pulmonary support; speech therapy; nonverbal, electronic, or mechanical communication systems for anarthric pts; and dietary management to ensure adequate energy intake. Attention to use of rehabilitative devices (braces, splints, canes, walkers, mechanized wheelchairs) is essential to improve care.
For a more detailed discussion, see Brown RH Jr: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases, Chap. 365, p. 2412, in HPIM- 15.